AVEO's Tivozanib Demonstrates Anti-Tumor Activity In Engineered Lung Tumors Exhibiting Treatment Resistant Mutations

Main Category: Lung Cancer
Also Included In: Cancer / Oncology;  MRSA / Drug Resistance;  Genetics
Article Date: 03 Aug 2009 - 19:00 PDT

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AVEO Pharmaceuticals, Inc., a biopharmaceutical company leveraging breakthrough discoveries in cancer biology to discover, develop and commercialize targeted oncology therapies, today announced data which demonstrates that tivozanib (AV-951) - the company's oral, triple VEGF receptor inhibitor - exhibits potent anti-angiogenic and anti-tumor activity in AVEO's proprietary in vivo lung cancer models. Specifically, treatment with tivozanib resulted in complete tumor growth inhibition or tumor regression (shrinkage) in lung tumors driven by EGFR or KRAS mutations, which are especially difficult to treat. These data are being presented today at the 13th World Conference on Lung Cancer (WCLC) in San Francisco, abstract number PD10.1.5.

"Non-small cell lung cancer is a highly heterogeneous disease and one of the most difficult cancers to treat. Common genetic alterations responsible for the disease, such as those driven by KRAS or certain EGFR mutations, typically render anticancer treatments powerless," stated Murray O. Robinson, Ph.D., senior vice president, oncology at AVEO. "Utilizing our proprietary cancer biology platform, we have created and treated genetically-engineered lung cancer mouse models driven by treatment resistant EGFR or KRAS, resulting in a much more realistic, human-like environment in which we can evaluate tivozanib efficacy. We are very pleased with and encouraged by the robust activity demonstrated by tivozanib in these difficult-to-treat tumor alleles."

Tivozanib is a novel, oral triple VEGF receptor inhibitor which recently completed a Phase 2 clinical study and is expected to enter a Phase 3 clinical trial later this year in patients with advanced kidney cancer. Tivozanib is being studied in several ongoing Phase 1b/2a clinical trials. Clinical results to date suggest tivozanib is a potent, well tolerated anticancer agent with broad potential as a treatment for solid tumors.

"Our innovative, proprietary cancer biology platform helps us create more relevant models of cancer in which we can evaluate the efficacy of our drug candidates preclinically, thereby increasing the probability of success in the clinic," stated Tuan Ha-Ngoc, president and chief executive officer of AVEO Pharmaceuticals. "The robust anti-angiogenic and anti-tumor activity of tivozanib in AVEO-engineered models of TKI-resistant lung tumors, paired with the early results observed with tivozanib in patients with lung cancer from the previously reported Phase 1 trial, highlights the potential role of tivozanib in the treatment of this difficult-to-treat cancer."

In this study, AVEO developed genetically engineered lung adenocarcinoma models driven by either treatment resistant EGFRT790M or KRAS mutant proteins by creating chimeric mice incorporating genetically modified ES cells. Tumors driven by EGFR or KRAS were propagated in vivo, to examine tivozanib activity in both subcutaneous and orthotopic settings. Treatment of subcutaneous lung KRAS tumors with tivozanib 2mg/kg and 5mg/kg daily PO for two weeks resulted in complete tumor growth inhibition and 44 percent tumor regressions respectively.

Lung EGFR tumors were tested in an orthotopic setting by intravenous seeding. Tivozanib treatment was initiated after tumor establishment was detected by in vivo imaging; 5 mg/kg daily dosing for more than 10 days resulted in prolonged survival. Histologic analysis showed the same dramatic anti-angiogenic changes as in the subcutaneous KRAS tumors, indicating that tivozanib is effective in killing orthotopic lung tumors that are resistant to EGFR targeted kinase inhibitors (TKIs).

In a previously reported Phase 1 dose-escalation study evaluating tivozanib in 41 patients with advanced solid tumors clinical benefit (i.e., partial response or stable disease lasting for three months or longer) was achieved across multiple tumor types, including in those patients with lung cancer. Overall, tumor shrinkage was observed in 33 percent of all patients during treatment with tivozanib. A Phase 1b/2a trial evaluating tivozanib as monotherapy in patients with non-small cell lung cancer was initiated in March 2009 and is ongoing.

In May 2009, researchers presented complete Phase 2 data evaluating tivozanib in metastatic renal cell carcinoma (mRCC) at the 45th Annual Meeting of the American Society for Clinical Oncology (ASCO), which demonstrated prolonged progression-free survival of 11.8 months and an excellent safety profile in patients treated with tivozanib. The company expects to initiate a Phase 3 trial of tivozanib in advanced kidney cancer later this year.

About Tivozanib

Tivozanib (AV-951), an investigational new drug, is a novel, highly potent and selective inhibitor of VEGF receptors 1, 2 and 3, exhibiting picomolar inhibitory activity against all three receptors. Angiogenesis inhibition has demonstrated benefit for patients with a wide range of cancer types, including renal cell carcinoma, metastatic breast cancer, colorectal cancer, and non-small cell lung cancer. Due to its potency and specificity, AVEO believes tivozanib may enable maximal inhibition of the VEGF pathway, while avoiding side effects associated with off-target activity. Such a profile may enable tivozanib to be more readily combined with standard chemotherapy as well as other targeted therapies, potentially increasing the breadth of its clinical utility. In addition, AVEO has evaluated tivozanib using its Human Response Platform (HRP™), a unique set of engineered tumor models that provide further insight into potential clinical settings, combinability with other anti-cancer agents, tumor subtypes and responsive patient populations.

AVEO recently completed a Phase 2 placebo-controlled, randomized discontinuation trial assessing the efficacy and safety of once-daily, oral tivozanib in renal cell carcinoma (RCC). In addition, AVEO is currently conducting multiple ongoing clinical trials of tivozanib including a Phase 1b trial in combination with temsirolimus (Torisel™), an approved mTOR inhibitor, in patients with mRCC; a Phase 1b trial in combination with the FOLFOX6 chemotherapy regimen in patients with advanced colorectal cancer and other gastrointestinal cancers; a Phase 1b/2a trial in combination with paclitaxel (Taxol™) in patients with metastatic breast cancer; and a Phase 1b/2a trial as monotherapy in patients with non-small cell lung cancer.

Source
AVEO Pharmaceuticals, Inc.

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